Affinage

GUCY2C

Guanylyl cyclase C · UniProt P25092

Length
1073 aa
Mass
123.4 kDa
Annotated
2026-06-10
100 papers in source corpus 25 papers cited in narrative 25 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GUCY2C (GC-C) is a transmembrane receptor guanylyl cyclase that serves as the principal intestinal receptor for the paracrine peptide hormones guanylin and uroguanylin and for bacterial heat-stable enterotoxin (STa), binding ligand through its extracellular domain and converting GTP to cGMP via its intracellular catalytic domain to coordinate intestinal fluid secretion, epithelial homeostasis, and tumor suppression (PMID:7906006, PMID:8103637). Receptor-generated cGMP activates cGMP-dependent protein kinase II to drive CFTR-dependent ion and water secretion, and the clinical importance of this output is established by human mutations: activating missense alleles that elevate cGMP cause familial and congenital secretory diarrhea, while loss-of-function alleles that abrogate cyclase activity cause meconium ileus (PMID:22436048, PMID:22521417, PMID:25994218). In its tumor-suppressive role, GUCY2C signaling restrains AKT activation, and loss of GUCY2C derepresses AKT-driven epithelial proliferation, glycolysis, and carcinogen-induced tumorigenesis, effects reversed by genetic or pharmacologic AKT disruption (PMID:19737566). Through AKT repression GUCY2C also enforces barrier integrity by maintaining tight-junction proteins and limiting MLCK/MLC-dependent junction disassembly, and suppresses stromal desmoplasia by limiting epithelial TGF-β secretion that otherwise drives a fibroblast HGF/cMET paracrine loop (PMID:22384056, PMID:21305056, PMID:24085786). Tumorigenesis silences this axis at the hormone level: APC–β-catenin/TCF signaling and diet-induced ER stress repress guanylin/uroguanylin expression while sparing the receptor, and restoring hormone expression reinstates signaling and eliminates tumors (PMID:26773096, PMID:32037952, PMID:34954189). Beyond the epithelium, GUCY2C functions in a gut–brain endocrine axis in which nutrient-induced circulating prouroguanylin is processed to uroguanylin to activate hypothalamic and midbrain GUCY2C neurons regulating satiation and thermogenesis, and in intestinal neuropod cells where its cGMP signaling restrains nociceptive transmission to sensory neurons (PMID:21865642, PMID:31485718, PMID:36548082).

Mechanistic history

Synthesis pass · year-by-year structured walk · 20 steps
  1. 1993 Medium

    Establishing that GUCY2C is a cell-surface receptor binding bacterial enterotoxin through its extracellular domain defined its receptor architecture and ligand-engagement mechanism.

    Evidence Truncated GC-C expression in COS-7 cells with photoaffinity labeling by 125I-STa and SDS-PAGE dimer analysis

    PMID:7906006

    Open questions at the time
    • No structure of the full-length receptor or ligand-bound state
    • Cyclase activation mechanism downstream of binding not resolved here
  2. 1993 Medium

    Co-localization of GCC receptor and guanylin ligand in colonic epithelium established the system as an endogenous paracrine signaling axis rather than only a toxin target.

    Evidence In situ hybridization and Northern blot of receptor and guanylin mRNA in rat colon

    PMID:8103637

    Open questions at the time
    • mRNA co-expression does not demonstrate functional paracrine signaling in vivo
    • Spatial relationship of secreting and responding cells unresolved
  3. 2000 Medium

    Discovery that cGMP output, but not receptor expression, varies along the gut axis revealed post-translational regulation of GUCY2C catalytic activity.

    Evidence Northern/Western blot, 125I-STa binding, and STa-stimulated cGMP measurement across rat intestinal segments

    PMID:10965892

    Open questions at the time
    • Molecular basis of segment-specific activity regulation not identified
    • Physiological consequence of the activity gradient unclear
  4. 2009 High

    Genetic epistasis placed GUCY2C upstream of AKT as a tumor suppressor, answering how receptor loss promotes intestinal carcinogenesis.

    Evidence Gucy2c-/- and Gucy2c-/-Akt1-/- double-knockout mice with carcinogen treatment, immunoblot, microarray, and metabolic assays

    PMID:19737566

    Open questions at the time
    • Biochemical link from cGMP to AKT inactivation not defined
    • Whether AKT repression accounts for all tumor-suppressive functions unknown
  5. 2011 High

    Identification of a gut-brain uroguanylin axis showed GUCY2C controls satiation, extending its role beyond the epithelium to systemic energy balance.

    Evidence Gucy2c knockout mice, intracerebroventricular hormone delivery, food intake/metabolic readouts, proteolytic processing assays

    PMID:21865642

    Open questions at the time
    • Identity of central GUCY2C-expressing neurons not yet mapped at this stage
    • Processing enzyme for hypothalamic prouroguanylin conversion not defined
  6. 2011 High

    Linking GUCY2C/guanylin loss to MLCK activation and tight-junction disassembly defined a mechanism for receptor control of barrier permeability.

    Evidence GCC-/- and UGN-/- mice, permeability assays, RT-PCR, immunoblot, and GCC RNAi in Caco-2/HT-29 cells

    PMID:21305056

    Open questions at the time
    • Causal chain from cGMP to IFNγ/STAT1/MLCK not fully ordered
    • Relative contribution of immune versus epithelial-intrinsic effects unresolved
  7. 2012 High

    Demonstrating that AKT1 repression by GUCY2C raises occludin and claudin-4 connected the tumor-suppressor pathway to barrier integrity and genotoxic protection.

    Evidence Gucy2c-/- mice with permeability assays, tight-junction immunoblots, Caco2 in vitro validation, and carcinogen tumorigenesis

    PMID:22384056

    Open questions at the time
    • Mechanism by which AKT1 controls junctional protein levels not detailed
    • Apparent differences in claudin regulation versus other studies unreconciled
  8. 2012 High

    Human activating and loss-of-function mutations established cGMP dosage as the causal determinant of opposite intestinal secretory phenotypes (diarrhea versus meconium ileus).

    Evidence Linkage/exome sequencing in human kindreds with cGMP and guanylyl cyclase activity assays in HEK293T cells

    PMID:22436048 PMID:22521417

    Open questions at the time
    • Structural basis for how mutations alter cyclase activity not solved
    • Downstream CFTR activation inferred rather than directly measured in patient tissue
  9. 2012 Medium

    Detection of guanylin/GC-C in mesenteric macrophages raised the possibility of an extra-epithelial cell compartment contributing to metabolic protection.

    Evidence Microarray, double-transgenic rats overexpressing guanylin/GC-C in macrophages, co-culture, and siRNA knockdown

    PMID:23081987

    Open questions at the time
    • Unexpected macrophage expression requires independent replication
    • Mechanism linking macrophage GC-C to adipocyte lipid accumulation unclear
  10. 2013 High

    Dissecting an epithelial-to-fibroblast TGF-β/HGF/cMET loop explained how GUCY2C loss drives stromal desmoplasia and cancer cell proliferation.

    Evidence GUCY2C silencing in human colon cancer cells, co-culture, anti-TGF-β antibodies, Smad3 phosphorylation assays, and Akt silencing in Gucy2c-/- mice

    PMID:24085786

    Open questions at the time
    • In vivo contribution of the HGF/cMET loop to tumor growth not quantified
    • Whether the loop operates in human tumors not established
  11. 2014 High

    Showing constitutive clathrin-mediated internalization to lysosomes defined GUCY2C trafficking and enabled lysosome-activated immunotoxin targeting of colorectal cancer.

    Evidence Live-cell imaging, clathrin inhibition, lysosomal trafficking assays, and immunotoxin cytotoxicity in vitro and in mice

    PMID:25294806

    Open questions at the time
    • Regulation of internalization rate and recycling not characterized
    • Relationship between trafficking and signaling output unexplored
  12. 2015 High

    Demonstration that de novo activating mutations in distinct intracellular domains raise cGMP both ligand-independently and ligand-stimulated broadened the genotype spectrum for congenital sodium diarrhea.

    Evidence Whole-exome/Sanger sequencing and cGMP accumulation assays in HEK293T cells for multiple mutations across four patients

    PMID:25994218

    Open questions at the time
    • Domain-specific mechanisms of constitutive activation not resolved
    • Patient intestinal cGMP and ion transport not directly measured
  13. 2016 High

    Identifying diet-induced ER stress/UPR as a silencer of guanylin showed how high-calorie intake disables GUCY2C signaling to permit tumorigenesis, reversible by hormone restoration.

    Evidence Engineered mice on differing diets, transgenic epithelial guanylin restoration, ER stress pathway analysis, and tumor counts

    PMID:26773096

    Open questions at the time
    • Molecular link from UPR to guanylin transcriptional repression not detailed
    • Generalizability to human obesity-associated cancer untested here
  14. 2017 Medium

    Linking GUCY2C to p53 activation via MDM2 dissociation defined a radioprotective mechanism preventing mitotic catastrophe in intestinal epithelium.

    Evidence Gucy2c-/- mice, lethal irradiation, p53/MDM2 interaction assays, and oral STa ligand delivery

    PMID:28916678

    Open questions at the time
    • Single-lab finding awaiting independent confirmation
    • Biochemical bridge from cGMP signaling to MDM2 dissociation not established
  15. 2019 High

    Mapping central GUCY2C to PMV (leptin-receptor) and TH-positive VTA/SN neurons with their axonal projections resolved the neuronal substrates of the gut-brain axis.

    Evidence In situ hybridization, immunofluorescence, stereotaxic ablation of PMV or VTA/SN neurons, and anterograde tracing

    PMID:31485718

    Open questions at the time
    • Functional output of each neuronal circuit not assigned here
    • Source of ligand activating these central neurons not defined
  16. 2020 Medium

    Demonstrating GC-C in arcuate POMC neurons mediates diet-induced brown-fat thermogenesis extended the uroguanylin axis to energy expenditure.

    Evidence GC-C KO mice, iBAT activity, POMC GC-C immunohistochemistry, intranasal uroguanylin delivery, and metabolic measurements

    PMID:31940065

    Open questions at the time
    • Circuit connecting POMC GC-C to BAT not traced
    • Reconciliation of POMC versus PMV/VTA neuronal sites of action incomplete
  17. 2020 High

    Identifying APC–β-catenin/TCF repression of guanylin (sparing the receptor) placed hormone loss at the earliest stage of colorectal tumorigenesis and showed biallelic APC loss is required.

    Evidence Conditional monoallelic/biallelic Apc-deletion mouse models, RNA-seq, and FAP patient tissue

    PMID:32037952

    Open questions at the time
    • Direct transcriptional mechanism at the guanylin locus not yet mapped here
    • Therapeutic reversibility not tested in this study
  18. 2021 High

    Locating a β-catenin/TCF-controlled locus control region and reactivating it by CRISPR epigenome editing defined the mechanism and reversibility of hormone silencing.

    Evidence RNA-seq across four colon cancer models, luciferase reporters, ChIP-seq, CRISPR knockout, and CRISPR epigenome editing

    PMID:34954189

    Open questions at the time
    • In vivo efficacy of epigenome reactivation not demonstrated
    • Whether restored hormone suppresses established tumors not addressed here
  19. 2021 High

    A knock-in mouse of the activating diarrhea mutation showed elevated cGMP drives fecal water/sodium loss, dysbiosis, ISG induction, and colitis susceptibility via PKG II, modeling human disease consequences.

    Evidence Activating Gucy2c knock-in mouse with microbiome analysis, colonic gene expression, DSS colitis, and transit assays

    PMID:34546338

    Open questions at the time
    • Causal order of dysbiosis versus ISG induction not resolved
    • Direct demonstration of PKG II as the effector limited to inference
  20. 2023 High

    Showing neuropod-cell GUCY2C restrains sensory neuron excitability and visceral pain assigned a cell-type-specific neural function to the receptor and explained linaclotide analgesia.

    Evidence Cell-type-specific expression analysis, neuropod cell–DRG co-culture electrophysiology, selective neuropod GUCY2C knockout, and visceral pain behavior

    PMID:36548082

    Open questions at the time
    • Signal transmitted from neuropod cell to DRG neuron not identified
    • Mechanism of cGMP action within neuropod cells not detailed

Open questions

Synthesis pass · forward-looking unresolved questions
  • The biochemical chain linking receptor-generated cGMP to its diverse effectors (AKT inactivation, p53/MDM2 dissociation, neuropod-to-neuron transmission) remains the central unresolved mechanism.
  • No defined molecular intermediary between cGMP/PKG II and AKT repression
  • No structural model of ligand-bound active receptor
  • Nature of the neuropod-cell-to-sensory-neuron signal unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0009975 cyclase activity 4 GO:0001618 virus receptor activity 2 GO:0038024 cargo receptor activity 2 GO:0060089 molecular transducer activity 2
Localization
GO:0005886 plasma membrane 3 GO:0005764 lysosome 1
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 3 R-HSA-382551 Transport of small molecules 3 R-HSA-1430728 Metabolism 2
Partners
AKT1CFTRGUCA2AGUCA2B

Evidence

Reading pass · 25 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2011 GUCY2C functions as an intestinal receptor for uroguanylin in a gut-brain endocrine axis regulating satiation; silencing GUCY2C in mice caused hyperphagia and obesity, and nutrient intake induced intestinal prouroguanylin secretion into circulation where it is proteolytically converted to uroguanylin in the hypothalamus to activate GUCY2C and anorexigenic pathways. Gucy2c knockout mice, intracerebroventricular hormone delivery, measurement of food intake and metabolic parameters, proteolytic processing assays The Journal of clinical investigation High 21865642
2009 GUCY2C suppresses intestinal tumorigenesis by inactivating AKT signaling; loss of GUCY2C in mice activated AKT phosphorylation, increased epithelial proliferation and glycolysis, and increased carcinogen-induced tumorigenesis, all of which were rescued by genetic or pharmacological AKT disruption. Gucy2c−/− mice, Gucy2c−/−Akt1−/− double-knockout mice, immunoblot, microarray, functional metabolic assays, carcinogen (azoxymethane) treatment Gastroenterology High 19737566
2012 GUCY2C regulates intestinal barrier integrity by repressing AKT1, thereby increasing tight junction proteins occludin and claudin-4; Gucy2c−/− mice showed barrier hyperpermeability, reduced junctional proteins, and increased systemic genotoxicity and spontaneous/carcinogen-induced tumorigenesis. Gucy2c−/− mice, permeability assays, immunoblot for tight junction proteins, Caco2 cell in vitro experiments, carcinogen treatment for tumorigenesis PloS one High 22384056
2011 GCC (GUCY2C) signaling maintains intestinal barrier function by regulating MLCK activation and tight junction disassembly; GCC−/− and UGN−/− mice had increased intestinal permeability associated with elevated IFNγ, MLCK, STAT1 activation, increased MLC phosphorylation, and reduced claudin-2 and JAM-A expression. GCC−/− and UGN−/− mice, intestinal permeability assays, RT-PCR, immunoblot, GCC RNAi in Caco-2 and HT-29 cells PloS one High 21305056
2013 GUCY2C prevents intestinal desmoplasia by suppressing Akt-dependent TGF-β secretion from epithelial cells; silencing GUCY2C increased TGF-β secretion that activated fibroblast TGF-β type I receptors and Smad3 phosphorylation, which in turn induced fibroblast secretion of HGF that drove colon cancer cell proliferation through cMET-dependent signaling. GUCY2C silencing in human colon cancer cells, co-culture assays, anti-TGF-β antibodies, genetic silencing of Akt in Gucy2c−/− mice, phosphorylation assays Cancer research High 24085786
2012 Activating heterozygous missense mutation (c.2519G→T) in GUCY2C causes familial diarrhea syndrome; mutant GC-C receptor produced markedly increased cGMP upon ligand exposure in HEK293T cells, consistent with hyperactivation of CFTR leading to increased chloride and water secretion. Linkage analysis, exome sequencing, functional cGMP assays in HEK293T cells expressing mutant receptor The New England journal of medicine High 22436048
2012 Loss-of-function homozygous mutations in GUCY2C that dramatically reduce or abrogate guanylyl cyclase enzymatic activity cause autosomal-recessive meconium ileus; GUCY2C activates CFTR through local cGMP generation in the intestine. Exome/Sanger sequencing, enzymatic activity assays, genetic mapping in consanguineous Bedouin kindreds American journal of human genetics High 22521417
2015 De novo activating missense mutations in different intracellular domains of GUCY2C cause congenital sodium diarrhea by enhancing intracellular cGMP accumulation in both a ligand-independent and ligand-stimulated manner. Whole-exome sequencing, Sanger sequencing, functional cGMP accumulation assays in HEK293T cells expressing mutant receptors Gut High 25994218
2014 GUCY2C internalizes from the cell surface to lysosomes via clathrin-mediated endocytosis, independently of ligand binding and receptor activation; this mechanism was exploited to deliver an immunotoxin (anti-GUCY2C antibody conjugated via reducible disulfide to ricin A chain) that was activated in lysosomes to kill colorectal cancer cells. Live cell imaging, clathrin inhibition experiments, lysosomal trafficking assays, immunotoxin cytotoxicity assays in vitro and in vivo mouse model Oncotarget High 25294806
2019 GUCY2C is expressed in two distinct neuronal circuits in the brain: hypothalamic GUCY2C mRNA is confined to ventral premammillary nucleus (PMV) neurons co-expressing anorexigenic leptin receptors, and midbrain GUCY2C is produced in tyrosine hydroxylase-positive VTA/SN neurons; GUCY2C protein is distributed along axonal projections from these two origins. In situ hybridization, immunofluorescence, stereotaxic ablation of PMV or VTA/SN neurons, anterograde tracer analysis Brain structure & function High 31485718
2016 Diet-induced obesity silences guanylin expression in colon through calorie-dependent induction of endoplasmic reticulum stress and the unfolded protein response in intestinal epithelial cells, thereby silencing GUCY2C signaling; transgenic restoration of guanylin expression specifically in intestinal epithelial cells restored GUCY2C signaling and eliminated intestinal tumors in mice on high-calorie diet. Genetically engineered mice on different diets, transgenic guanylin expression, ER stress pathway analysis, tumor counts Cancer research High 26773096
2020 APC-β-catenin-TCF signaling transcriptionally represses guanylin hormone expression (but not the GUCY2C receptor itself) at the earliest stages of colorectal tumorigenesis, silencing GUCY2C signaling; biallelic but not monoallelic APC loss was required for hormone repression. Conditional genetic mouse models (monoallelic and biallelic Apc deletion), RNA-seq, FAP patient tissue analysis Cancer biology & therapy High 32037952
2021 β-Catenin/TCF signaling mediates transcriptional repression of GUCY2C hormone ligands (guanylin and uroguanylin) through a locus control region upstream of the guanylin promoter; CRISPR epigenome editing of this region reconstituted hormone expression, overcoming gene inactivation by mutant β-catenin/TCF. RNA-seq in 4 conditional colon cancer cell models, luciferase reporters, ChIP-seq, CRISPR/Cas9 knockout, CRISPR epigenome editing Cellular and molecular gastroenterology and hepatology High 34954189
2021 Activating mutation in Gucy2c equivalent to the Norwegian family mutation produces elevated intestinal cGMP, enhanced fecal water and sodium content, dysbiosis, up-regulation of IFN-stimulated genes, and increased susceptibility to DSS-induced colitis; intestinal cGMP acts via cGMP-dependent protein kinase II. Novel knock-in mouse model with activating Gucy2c mutation, fecal microbiome analysis, colonic gene expression, DSS colitis model, intestinal transit assays The Journal of experimental medicine High 34546338
2023 Intestinal GUCY2C is selectively enriched in neuropod cells (a type of enteroendocrine cell); GUCY2C-sufficient neuropod cells induced hyperexcitability in co-cultured dorsal root ganglia neurons, and the GUCY2C agonist linaclotide eliminated this neuronal hyperexcitability in a manner requiring neuropod cell GUCY2C but independent of bulk epithelial cells or extracellular cGMP; selective elimination of GUCY2C in neuropod cells increased nociceptive signaling and visceral pain refractory to linaclotide. Cell-type specific GUCY2C expression analysis, neuropod cell-DRG neuron co-culture, electrophysiology (rheobase measurement, action potential counting), selective neuropod cell GUCY2C knockout, visceral pain behavioral assays The Journal of clinical investigation High 36548082
2017 GUCY2C signaling opposes radiation-induced GI syndrome by activating p53 through its dissociation from MDM2, preventing mitotic catastrophe (but not apoptosis) in intestinal epithelial cells; oral delivery of exogenous GUCY2C ligand (heat-stable enterotoxin ST) reduced radiation-induced mortality. Gucy2c−/− mice, lethal irradiation model, p53/MDM2 interaction assays, oral ligand delivery, cell death mechanistic assays Cancer research Medium 28916678
1993 GC-C (GUCY2C) expressed at the surface of COS-7 cells binds heat-stable enterotoxin (STa) via its extracellular domain; the intracellular region is not required for dimer formation, and the truncated GC-C forms dimers on the cell surface and is glycosylated in mammalian cells. Truncated GC-C expression in COS-7 cells, photoaffinity labeling with 125I-STa, SDS-PAGE analysis of dimer formation Microbial pathogenesis Medium 7906006
2000 GC-C mRNA and STa-binding sites are uniformly expressed throughout the rat intestine, but GC-C-mediated cGMP synthesis peaks at the proximal and distal extremes (duodenum and colon) but is nearly absent in the ileum, indicating post-translational regulation of GC-C activity along the intestinal axis. Northern blot, Western blot, [125I]STa binding, STa-dependent cGMP elevation measurements across intestinal segments Endocrinology Medium 10965892
1993 GCC mRNA is expressed specifically in intestinal epithelial cells throughout colonic crypts and surface epithelium, while its ligand guanylin mRNA is also expressed in the same tissue, establishing their co-localization as a paracrine signaling system. In situ hybridization, Northern blot analysis of GCA, GCC, and guanylin mRNA in rat colon The American journal of physiology Medium 8103637
2007 An alternative non-GC-C receptor for STa exists in the intestine; STa-stimulated duodenal bicarbonate secretion in GC-C knockout mice occurred through a CFTR-independent pathway (blocked by DIDS but not glibenclamide), while uroguanylin- and guanylin-stimulated secretion was CFTR-dependent. [125I]STa binding in GC-C KO and WT mice, in vitro and in vivo duodenal bicarbonate secretion measurements, pharmacological inhibitors FASEB journal Medium 18096816
2001 Two isoforms of GC-C (GC-C1 and GC-C2) were cloned from European eel intestine; GC-C2 intestinal expression increased 100% upon seawater transfer and 60% during developmental maturation of yellow to silver eels, and was restricted to anterior/mid-gut segments in freshwater but extended to posterior gut in seawater, indicating physiological regulation of GC-C expression. cDNA cloning, Northern blot, RT-PCR, acclimation experiments Comparative biochemistry and physiology Low 11399493
2020 GUCY2C expressed in the hypothalamus (specifically proopiomelanocortin neurons of the arcuate nucleus) mediates diet-induced thermogenesis; GC-C KO mice showed diminished activation of brown adipose tissue (iBAT) after a meal, and intranasal uroguanylin increased iBAT activity in a GC-C-dependent manner correlated with reduced blood glucose. GC-C KO mice, iBAT activity measurements, hypothalamic GC-C immunohistochemistry in POMC neurons, intranasal UGN delivery, metabolic measurements Pflugers Archiv Medium 31940065
2012 Guanylin and GC-C expressed in mesenteric macrophages (not only intestinal epithelium) contribute to resistance to high-fat diet-induced obesity; double-transgenic rats overexpressing guanylin and GC-C in macrophages resisted HFD-induced obesity with altered expression of lipid metabolism genes, and lipid accumulation in adipocytes was inhibited by co-culture with macrophages expressing guanylin/GC-C. Microarray screen, histological analysis, double-transgenic rat generation, co-culture assays, siRNA knockdown of guanylin and GC-C Journal of lipid research Medium 23081987
2009 GUCY2C (GCC) functions as a receptor for the paracrine hormones guanylin and uroguanylin, converting GTP to cGMP, and acts as a tumor suppressor coordinating proliferative homeostasis; its signaling reverses the tumorigenic phenotype of human colon cancer cells by regulating proliferation and metabolism. GCC receptor activation in human colon cancer cells, cell cycle analysis, DNA synthesis assay, colony formation, metabolic assays Drug news & perspectives Low 19771320
2009 GUCY2C shares domain organization with other receptor guanylate cyclases (extracellular ligand-binding domain, transmembrane domain, intracellular catalytic domain) and is the primary intestinal receptor for guanylin, uroguanylin, and bacterial heat-stable enterotoxins; GC-C or ligand knockouts in mice modulate responses to stable toxin peptides, dietary salt, and intestinal cell development/differentiation. Gene knockout mice, review of structural and functional domain analyses Molecular and cellular biochemistry Low 19960363

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1998 A novel mode of DNA recognition by a beta-sheet revealed by the solution structure of the GCC-box binding domain in complex with DNA. The EMBO journal 340 9736626
1998 Unique mode of GCC box recognition by the DNA-binding domain of ethylene-responsive element-binding factor (ERF domain) in plant. The Journal of biological chemistry 281 9756931
2013 Salicylic acid suppresses jasmonic acid signaling downstream of SCFCOI1-JAZ by targeting GCC promoter motifs via transcription factor ORA59. The Plant cell 274 23435661
1994 Isolation of a GCC repeat showing expansion in FRAXF, a fragile site distal to FRAXA and FRAXE. Nature genetics 159 7874164
2012 Familial diarrhea syndrome caused by an activating GUCY2C mutation. The New England journal of medicine 158 22436048
2003 New members of the tomato ERF family show specific expression pattern and diverse DNA-binding capacity to the GCC box element. FEBS letters 142 12935902
2004 The ethylene-, jasmonate-, abscisic acid- and NaCl-responsive tomato transcription factor JERF1 modulates expression of GCC box-containing genes and salt tolerance in tobacco. Planta 137 15300440
2011 A uroguanylin-GUCY2C endocrine axis regulates feeding in mice. The Journal of clinical investigation 128 21865642
2018 Human GUCY2C-Targeted Chimeric Antigen Receptor (CAR)-Expressing T Cells Eliminate Colorectal Cancer Metastases. Cancer immunology research 121 29615399
2009 The hormone receptor GUCY2C suppresses intestinal tumor formation by inhibiting AKT signaling. Gastroenterology 102 19737566
2002 Determinants in the sequence specific binding of two plant transcription factors, CBF1 and NtERF2, to the DRE and GCC motifs. Biochemistry 89 11914065
2004 Tomato stress-responsive factor TSRF1 interacts with ethylene responsive element GCC box and regulates pathogen resistance to Ralstonia solanacearum. Plant molecular biology 85 15604719
1995 A GCC element and a G-box motif participate in ethylene-induced expression of the PRB-1b gene. Plant molecular biology 80 7787179
2011 Loss of guanylyl cyclase C (GCC) signaling leads to dysfunctional intestinal barrier. PloS one 78 21305056
1993 Peptide-regulated guanylate cyclase pathways in rat colon: in situ localization of GCA, GCC, and guanylin mRNA. The American journal of physiology 78 8103637
2004 The ethylene-responsive factor like protein 1 (CaERFLP1) of hot pepper (Capsicum annuum L.) interacts in vitro with both GCC and DRE/CRT sequences with different binding affinities: possible biological roles of CaERFLP1 in response to pathogen infection and high salinity conditions in transgenic tobacco plants. Plant molecular biology 75 15604665
2012 Meconium ileus caused by mutations in GUCY2C, encoding the CFTR-activating guanylate cyclase 2C. American journal of human genetics 74 22521417
2015 Congenital secretory diarrhoea caused by activating germline mutations in GUCY2C. Gut 73 25994218
2016 GUCY2C-directed CAR-T cells oppose colorectal cancer metastases without autoimmunity. Oncoimmunology 72 27853651
2012 GUCY2C opposes systemic genotoxic tumorigenesis by regulating AKT-dependent intestinal barrier integrity. PloS one 72 22384056
1996 Solution structures of the individual single strands of the fragile X DNA triplets (GCC)n.(GGC)n. Nucleic acids research 70 8604324
2004 Methyl jasmonate induced expression of the tobacco putrescine N -methyltransferase genes requires both G-box and GCC-motif elements. Plant molecular biology 67 15604714
2001 The fragile X chromosome (GCC) repeat folds into a DNA tetraplex at neutral pH. Nucleic acids research 61 11713318
2006 The conserved Ala37 in the ERF/AP2 domain is essential for binding with the DRE element and the GCC box. FEBS letters 60 16457823
2019 Split tolerance permits safe Ad5-GUCY2C-PADRE vaccine-induced T-cell responses in colon cancer patients. Journal for immunotherapy of cancer 53 31010434
2009 Receptor guanylyl cyclase C (GC-C): regulation and signal transduction. Molecular and cellular biochemistry 53 19960363
2016 Obesity-Induced Colorectal Cancer Is Driven by Caloric Silencing of the Guanylin-GUCY2C Paracrine Signaling Axis. Cancer research 51 26773096
2000 Expression of GC-C, a receptor-guanylate cyclase, and its endogenous ligands uroguanylin and guanylin along the rostrocaudal axis of the intestine. Endocrinology 51 10965892
1999 Elicitor-responsive, ethylene-independent activation of GCC box-mediated transcription that is regulated by both protein phosphorylation and dephosphorylation in cultured tobacco cells. The Plant journal : for cell and molecular biology 50 10652129
2014 The paracrine hormone for the GUCY2C tumor suppressor, guanylin, is universally lost in colorectal cancer. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 47 25304930
2020 A Novel GUCY2C-CD3 T-Cell Engaging Bispecific Construct (PF-07062119) for the Treatment of Gastrointestinal Cancers. Clinical cancer research : an official journal of the American Association for Cancer Research 46 31996389
2015 Dose-dependent testosterone sensitivity of the steroidal passport and GC-C-IRMS analysis in relation to the UGT2B17 deletion polymorphism. Drug testing and analysis 45 26198073
2022 Recommendations on qPCR/ddPCR assay validation by GCC. Bioanalysis 43 35703321
2019 The hepatocyte-specifically expressed lnc-HSER alleviates hepatic fibrosis by inhibiting hepatocyte apoptosis and epithelial-mesenchymal transition. Theranostics 42 31695787
2024 Chimeric Antigen Receptor T Cells Targeting CD19 and GCC in Metastatic Colorectal Cancer: A Nonrandomized Clinical Trial. JAMA oncology 38 39298141
2013 Influence of axial length on ganglion cell complex (GCC) thickness and on GCC thickness to retinal thickness ratios in young adults. Japanese journal of ophthalmology 35 24242185
1996 In vitro expansion of GGC:GCC repeats: identification of the preferred strand of expansion. Nucleic acids research 35 8759019
2008 Abscisic acid regulates TSRF1-mediated resistance to Ralstonia solanacearum by modifying the expression of GCC box-containing genes in tobacco. Journal of experimental botany 31 18252700
1998 A nitrilase-like protein interacts with GCC box DNA-binding proteins involved in ethylene and defense responses. Plant physiology 31 9808731
2003 Sample preparation techniques for the determination of natural 15N/14N variations in amino acids by gas chromatography-combustion-isotope ratio mass spectrometry (GC-C-IRMS). Isotopes in environmental and health studies 30 14521284
2020 Chimeric Ad5.F35 vector evades anti-adenovirus serotype 5 neutralization opposing GUCY2C-targeted antitumor immunity. Journal for immunotherapy of cancer 29 32819976
1988 Effects of 5' flanking sequences and changes in the 5' internal control region on the transcription of rice tRNA % MathType!MTEF!2!1!+-% feaafiart1ev1aaatCvAUfeBSjuyZL2yd9gzLbvyNv2CaerbuLwBLn% hiov2DGi1BTfMBaeXatLxBI9gBaerbd9wDYLwzYbItLDharqqtubsr% 4rNCHbGeaGqiVu0Je9sqqrpepC0xbbL8F4rqqrFfpeea0xe9Lq-Jc9% vqaqpepm0xbba9pwe9Q8fs0-yqaqpepae9pg0FirpepeKkFr0xfr-x% fr-xb9adbaqaaeGaciGaaiaabeqaamaabaabaaqcKbay-haafaqabe% GabaaabaGaae4raiaabYgacaqG5baabaGaae4raiaaboeacaqGdbaa% aaaa!3CC7!\[\begin{array}{*{20}c} {{\text{Gly}}} \\ {{\text{GCC}}} \\ \end{array} \]. Plant molecular biology 28 24272491
2021 Gut-associated cGMP mediates colitis and dysbiosis in a mouse model of an activating mutation in GUCY2C. The Journal of experimental medicine 27 34546338
2019 Two distinct GUCY2C circuits with PMV (hypothalamic) and SN/VTA (midbrain) origin. Brain structure & function 27 31485718
2022 Paternal High-Fat Diet Altered Sperm 5'tsRNA-Gly-GCC Is Associated With Enhanced Gluconeogenesis in the Offspring. Frontiers in molecular biosciences 26 35480893
2001 Expansion mutation frequency and CGG/GCC repeat polymorphism in FMR1 and FMR2 genes in an Indian population. Genetic epidemiology 26 11119302
2014 GUCY2C lysosomotropic endocytosis delivers immunotoxin therapy to metastatic colorectal cancer. Oncotarget 25 25294806
2010 Identification of a GCC transcription factor responding to fruit colour change events in citrus through the transcriptomic analyses of two mutants. BMC plant biology 25 21159189
2007 Heat-stable enterotoxin of Escherichia coli (STa) can stimulate duodenal HCO3(-) secretion via a novel GC-C- and CFTR-independent pathway. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 24 18096816
2014 Tumor radiation therapy creates therapeutic vaccine responses to the colorectal cancer antigen GUCY2C. International journal of radiation oncology, biology, physics 23 24661671
2014 Meconium ileus in a Lebanese family secondary to mutations in the GUCY2C gene. European journal of human genetics : EJHG 23 25370039
2013 GUCY2C: at the intersection of obesity and cancer. Trends in endocrinology and metabolism: TEM 22 23375388
2013 Intestinal GUCY2C prevents TGF-β secretion coordinating desmoplasia and hyperproliferation in colorectal cancer. Cancer research 22 24085786
2023 Intestinal neuropod cell GUCY2C regulates visceral pain. The Journal of clinical investigation 21 36548082
2019 Silencing the GUCA2A-GUCY2C tumor suppressor axis in CIN, serrated, and MSI colorectal neoplasia. Human pathology 21 30716341
2007 Novel repressor of the human FMR1 gene - identification of p56 human (GCC)(n)-binding protein as a Krüppel-like transcription factor ZF5. The FEBS journal 20 17714511
2008 Characterization of differential ripening pattern in association with ethylene biosynthesis in the fruits of five naturally occurring banana cultivars and detection of a GCC-box-specific DNA-binding protein. Plant cell reports 19 18449546
2001 Cloning and expression of two isoforms of guanylate cyclase C (GC-C) from the European eel (Anguilla anguilla). Comparative biochemistry and physiology. Part B, Biochemistry & molecular biology 19 11399493
2018 Comprehensive haematological indices reference intervals for a healthy Omani population: First comprehensive study in Gulf Cooperation Council (GCC) and Middle Eastern countries based on age, gender and ABO blood group comparison. PloS one 18 29621271
2021 Circulatory exosomal tRF-Glu-CTC-005 and tRF-Gly-GCC-002 serve as predictive factors of successful microdissection testicular sperm extraction in patients with nonobstructive azoospermia. Fertility and sterility 17 34955241
2017 Prolonged intestinal transit and diarrhea in patients with an activating GUCY2C mutation. PloS one 17 28957388
1998 Fragile X DNA triplet repeats, (GCC)n, form hairpins with single hydrogen-bonded cytosine.cytosine mispairs at the CpG sites: isotope-edited nuclear magnetic resonance spectroscopy on (GCC)n with selective 15N4-labeled cytosine bases. Journal of molecular biology 17 9761677
2021 Circulating PTGS2, JAG1, GUCY2C and PGF mRNA in Peripheral Blood and Serum as Potential Biomarkers for Patients with Metastatic Colon Cancer. Journal of clinical medicine 16 34067294
2002 Thermodynamic contributions for the incorporation of GTA triplets within canonical TAT/TAT and C+GC/C+GC base-triplet stacks of DNA triplexes. Biochemistry 16 12369838
2021 Discovery and optimization of a novel anti-GUCY2c x CD3 bispecific antibody for the treatment of solid tumors. mAbs 15 33459147
2020 Activation of brown adipose tissue in diet-induced thermogenesis is GC-C dependent. Pflugers Archiv : European journal of physiology 15 31940065
2016 GUCY2C ligand replacement to prevent colorectal cancer. Cancer biology & therapy 15 27104761
2001 The measurement of muscle protein synthesis in broilers with a flooding dose technique: use of 15N-labelled phenylalanine, GC-MS and GC-C-IRMS. Isotopes in environmental and health studies 15 11924852
2024 tRF-Gly-GCC in Atretic Follicles Promotes Ferroptosis in Granulosa Cells by Down-Regulating MAPK1. International journal of molecular sciences 14 39201747
2022 Comparative Evaluation of Two SD-OCT Macular Parameters (GCC, GCL) and RNFL in Chiasmal Compression. Eye and brain 14 35282333
2022 Potential Functions of the tRNA-Derived Fragment tRF-Gly-GCC Associated With Oxidative Stress in Radiation-Induced Lung Injury. Dose-response : a publication of International Hormesis Society 14 36176737
2022 A Novel tiRNA-Gly-GCC-1 Promotes Progression of Urothelial Bladder Carcinoma and Directly Targets TLR4. Cancers 14 36230476
2021 GUCY2C as a biomarker to target precision therapies for patients with colorectal cancer. Expert review of precision medicine and drug development 14 34027103
2017 GUCY2C Signaling Opposes the Acute Radiation-Induced GI Syndrome. Cancer research 14 28916678
2009 GCC signaling in colorectal cancer: Is colorectal cancer a paracrine deficiency syndrome? Drug news & perspectives 14 19771320
1993 Expression of a truncated guanylate cyclase (GC-C), a receptor for heat-stable enterotoxin of enterotoxigenic Escherichia coli, and its dimer formation in COS-7 cells. Microbial pathogenesis 14 7906006
2024 5'-tRNAGly(GCC) halves generated by IRE1α are linked to the ER stress response. Nature communications 13 39468069
2020 Preclinical Antitumor Activity and Biodistribution of a Novel Anti-GCC Antibody-Drug Conjugate in Patient-derived Xenografts. Molecular cancer therapeutics 13 32788205
2011 GUCY2C-targeted cancer immunotherapy: past, present and future. Immunologic research 13 22038530
2008 Upregulation of the promoter activity of the carrot (Daucus carota) phenylalanine ammonia-lyase gene (DcPAL3) is caused by new members of the transcriptional regulatory proteins, DcERF1 and DcERF2, which bind to the GCC-box homolog and act as an activator to the DcPAL3 promoter. Journal of plant research 13 18584290
2024 A phenome-wide association study of methylated GC-rich repeats identifies a GCC repeat expansion in AFF3 associated with intellectual disability. Nature genetics 12 39313615
2021 Preclinical Evaluation of 89Zr-Df-IAB22M2C PET as an Imaging Biomarker for the Development of the GUCY2C-CD3 Bispecific PF-07062119 as a T Cell Engaging Therapy. Molecular imaging and biology 12 34143379
2016 An activating gucy2c mutation causes impaired contractility and fluid stagnation in the small bowel. Scandinavian journal of gastroenterology 12 27338166
2012 Involvement of guanylin and GC-C in rat mesenteric macrophages in resistance to a high-fat diet. Journal of lipid research 12 23081987
2010 Optimizing the binding activity of the AP2/ERF transcription factor with the GCC box element from Brassica napus by directed evolution. BMB reports 12 20797320
2023 Inhibition of tiRNA-Gly-GCC ameliorates neointimal formation via CBX3-mediated VSMCs phenotypic switching. Frontiers in cardiovascular medicine 11 36818350
2021 Novel GUCY2C variant causing familial diarrhea in a Mennonite kindred and a potential therapeutic approach. American journal of medical genetics. Part A 11 33949097
2021 Novel implications of a strictly monomorphic (GCC) repeat in the human PRKACB gene. Scientific reports 11 34667254
2020 APC-β-catenin-TCF signaling silences the intestinal guanylin-GUCY2C tumor suppressor axis. Cancer biology & therapy 11 32037952
2020 Silencing the intestinal GUCY2C tumor suppressor axis requires APC loss of heterozygosity. Cancer biology & therapy 11 32594830
2018 Genetic and transcriptional analysis of inflammatory bowel disease-associated pathways in patients with GUCY2C-linked familial diarrhea. Scandinavian journal of gastroenterology 11 30353760
2013 [Analysis of macular ganglion cell complex (GCC) with spectral-domain optical coherence tomography (SD-OCT) in glaucoma]. Journal francais d'ophtalmologie 11 23541535
2010 The rat kidney contains high levels of prouroguanylin (the uroguanylin precursor) but does not express GC-C (the enteric uroguanylin receptor). American journal of physiology. Renal physiology 11 21106860
2009 Previstage GCC colorectal cancer staging test: a new molecular test to identify lymph node metastases and provide more accurate information about the stage of patients with colorectal cancer. Molecular diagnosis & therapy 11 19351210
2024 Antigen-independent activation is critical for the durable antitumor effect of GUCY2C-targeted CAR-T cells. Journal for immunotherapy of cancer 10 39366753
2022 Recommendations on ELISpot assay validation by the GCC. Bioanalysis 10 35135309
2022 A (GCC) repeat in SBF1 reveals a novel biological phenomenon in human and links to late onset neurocognitive disorder. Scientific reports 10 36104480
2021 A β-Catenin-TCF-Sensitive Locus Control Region Mediates GUCY2C Ligand Loss in Colorectal Cancer. Cellular and molecular gastroenterology and hepatology 10 34954189
2009 GUCY2C reverse transcriptase PCR to stage pN0 colorectal cancer patients. Expert review of molecular diagnostics 10 19895223
2001 Extrahelical cytosine bases in DNA duplexes containing d[GCC](n).d[GCC](n) repeats: detection by a mechlorethamine crosslinking reaction. Nucleic acids research 10 11713322

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